There are a number of vision-threatening disorders or diseases of the eye of a mammal including, but not limited to diseases of the retina, retinal pigment epithelium (RPE) and choroid. Such vision threatening diseases include, for example, ocular neovascularization, ocular inflammation and retinal degenerations. Specific examples of these disease states include diabetic retinopathy, chronic glaucoma, retinal detachment, sickle cell retinopathy, age-related macular degeneration, retinal neovascularization, subretinal neovascularization; rubeosis iritis inflammatory diseases, chronic posterior and pan uveitis, neoplasms, retinoblastoma, pseudoglioma, neovascular glaucoma; neovascularization resulting following a combined vitrectomy and lensectomy, vascular diseases, retinal ischemia, choroidal vascular insufficiency, choroidal thrombosis, neovascularization of the optic nerve, diabetic macular edema, cystoid macular edema, macular edema, retinitis pigmentosa, retinal vein occlusion, proliferative vitreoretinopathy, angioid streak, and retinal artery occlusion, and, neovascularization due to penetration of the eye or ocular injury.
For example, age-related macular degeneration (AMD) is the leading cause of irreversible severe central vision loss in Caucasians fifty years old and older in the United States. According to the 1990 U.S. census, approximately 750,000 people over 65 years of age were estimated as severe visual impairment in one or both eyes from AMD. Also, the number of cases of AMD has been predicted to increase from 2.7 million in 1970 to 7.5 million by the year 2030.
Roughly 80 percent of the AMD cases involve non-neovascular conditions, for which there are no effective treatments. For the remaining cases involving neovascularization, currently available treatments are sub-optimal. Perhaps the best-known therapy is photodynamic therapy (PDT), however, while this therapy has received significant intention in both the ophthalmic and financial investment communities, it is useful in only about 20 percent of neovascular AMD cases. In addition, this particular therapy is not a simple or inexpensive treatment. The procedure generally needs to be repeated every three months for at least two years, with approximate total cost of $12,250.
A number of angiostatic agents are currently under investigation for the treatment of AMD. Thalidomide, for example, is known to be a powerful angiostatic agent. Its systemic side effects, however, include peripheral neuropathy, central nervous system depression, and embryotoxicity. In addition, these systemic side effects have limited the dosage administered to patients for the treatment of subretinal neovascularization. Systemic inhibition of angiogenesis in older patients can also interfere with the development of collateral circulation, which has a role in the prevention of central nervous system as well as cardiac ischemic events.
A number of techniques or methodologies have been developed to deliver drugs to the various tissues or structures that make up the mammalian eye as described hereinafter to treat a wide range of disorders or diseases of the eye. However, delivery of drugs, proteins and the like to the eye(s) of mammals so as to achieve the desired therapeutic or medical effect, especially to the retina and/or the choroid, has proven to be challenging, most of which is owed to the geometry, delicacy and/or behavior of the eye and its components. A brief description of various conventional methods or techniques for delivering drugs to the tissues of the eye and the shortcomings thereof are hereinafter described.
Oral ingestion of a drug or injection of a drug at a site other than the eye can provide a drug systemically; however, such a systemic administration does not provide effective levels of the drug specifically to the eye. In many ophthalmic disorders involving the retina, posterior tract, and optic nerve, adequate levels of the drug cannot be achieved or maintained by oral or parenteral routes of administration. Thus, further and repeated administration of the drug would be necessary to achieve the desired or adequate levels of concentration of the drug. Such further and repeated administrations of such drugs, however, may produce undesired systemic toxicity.
Ophthalmic conditions have also been treated using drugs applied directly to the eye in either liquid or ointment form. This route of administration (i.e., topical administration), however, is most effective in treating problems involving the superficial surface of the eye and diseases that involve the cornea and anterior segment of the eye, such as for example, conjunctivitis. In addition, topical eye drops may drain from the eye through the nasolacrimal duct and into the systemic circulation, further diluting the medication and risking unwanted systemic side effects. Furthermore, delivery of drugs in the form of topical eye drops is also of limited utility because the drug cannot easily cross the cornea or sclera and be made available to the vitreous, retina, or other subretinal structures such as the retinal pigment epithelium (“RPE”) or choroidal vasculature and/or is highly unstable and therefore not easily formulated for topical delivery. Moreover, data also indicates that it is not unusual for up to 85% of topically applied agents to be removed by the eye's blink mechanism/reflex.
Direct delivery of drugs to the eye by a topical insert has also been attempted; however, this method is not desirable. Such topical inserts require patient self-administration and thus education on their insertion into and removal from the eye. Consequently, this technique demands a certain degree of manual dexterity that can be problematic for geriatric patients who are particularly susceptible to certain eye disorders that appear age related (e.g., age related macular degeneration). Also, in many instances such topical inserts may cause eye irritation and such inserts are prone to inadvertent loss due to eyelid laxity. In addition, these devices provide a source of drug only to the cornea and anterior chamber, and thus do not provide any significant pharmacologic advantage over topical eye drops or ointments. Thus, such devices have limited utility for providing an effective source of drugs to the vitreous or tissues located in the posterior segment of the eye.
As a consequence most methods for treating eye disorders or diseases in the posterior segment, or the back-of-the-eye, involve intravitreal delivery of the drug. One such technique for intravitreal delivery is accomplished by intraocular injection of the drug or microspheres containing the drug directly into the vitreous or by locating a device or capsule containing the drug in the vitreous, such as that described in U.S. Pat. No. 5,770,589. Intravitreal injection of a drug is an effective means of delivering the drug to the posterior segment of the eye in high concentrations, but it is not without its shortcomings such as fast clearance rate and tissue toxicity.
In addition, it also is well known that many therapeutic drugs cannot easily diffuse across the retina. Thus, the dose being administered and maintained in the vitreous has to take into account the amount that can diffuse across the retinal boundary as well as how long the drug is retained in effective amounts within the vitreous. For example, it has been observed from animal studies that three days following an injection of triamcinolone, less than 1% of the triamcinolone present in the vitreous was associated with other tissues including the retina, pigment epithelium, and sclera. In addition to the relative effectiveness of drug delivery across the barrier, complications or side effects have been observed when using the direct injection into vitreous technique with some therapeutics.
For example, compounds classified as corticosteroids, such as triamcinolone, can effectively treat some forms of neovascularization such as corneal neovascularization. When these compounds were used to treat neovascularization of the posterior segment by direct injection, these compounds were observed to cause undesirable side effects in many patients. The adverse affects or undesirable side effects being observed included elevations in intraocular pressure and the formation of, or acceleration of the development of cataracts. Elevations in intraocular pressure are of particular concern in patients. Moreover, a risk exists that the use of corticosteroids in patients with normal intraocular pressure will cause elevations in pressure that result in damage to ocular tissue. Since therapy with corticosteroids is frequently long term, a potential exists for significant damage to ocular tissue as a result of prolonged elevations in intraocular pressure attributable to that therapy.
Consequently, efforts in the area of intravitreal delivery also have included delivery by locating a sustained release implant, capsule or other such device or mechanism that is in communication with the vitreous and which is configured so as to provide a release over time into the vitreous of the contained drug. Examples of such controlled release devices are described in U.S. Pat. Nos. 6,217,895; 5,773,019; 5,378,475; and in U.S. Patent Application Publication No. 2002/0061327.
A common feature of the techniques/instruments described therein, is that a surgical incision is required to be made at the outset of a procedure so that the implant, capsule or other such device can be inserted through the eye and located in the vitreous. These methods and techniques may also involve the use of sutures following completion of the procedure to seal or close the incision so as to prevent loss of vitreous material and promote wound closure healing. As is known to those skilled in the art, maintaining the volume and pressure of the posterior segment or vitreous is necessary to maintaining the shape and optical arrangement of the eye. Such a course of treatment also increases the duration and cost as well as the realistic risks of corneal ulceration, cataract formation, intraocular infection, and/or vitreous loss that accompany these procedures.
There is described in U.S. Pat. Nos. 5,273,530 and 5,409,457 an instrument and methodology to transplant donor cells, more specifically donor retina cells, in the subretinal space. It also is described therein that the instrument also can be used to inject or remove material from the vitreous. According to the described methodology, the instrument is shaped and dimensioned so it can be inserted into an eye orbit along an insertion path that extends along the periphery of the eye and so as to place the tip adjacent to the retina or subretinal region. The tip is then moved generally in the medial direction so the tip resides in the subretinal region or in the vitreous depending upon how much the tip is moved. In order to prevent over-insertion of the tip, a collar is provided about the tip so as to limit the distance the tip can be inserted into the eye.
There also is described in US Patent Application Publication 2002/0055724, an instrument for subretinal transplantation of retinal cells, epithelium and choroid within their normal planar configuration as a graft into the subretinal region of an eye. The described instrument is inserted into an opening in the eye using either a trans-corneal surgical approach or a trans-choroidal and scleral surgical approach. According to this technique the instrument is advanced under the retina to detach the retina so that the graft can be inserted. As noted in U.S. Pat. No. 5,273,530, the penetration of the anterior part or segment of the eye, using the transcorneal or the transscleral route creates the risks of corneal ulceration, cataract formation and other anterior penetration problems. Also using either approach, a surgical incision is created at the outset of a procedure so that the instrument can be inserted and sutures are used following completion of the procedure to seal or close the incision so as to prevent loss of vitreous material (i.e., aqueous humor).
There is described in U.S. Pat. No. 5,516,522 a biodegradable porous drug delivery device for controllably releasing a pharmacological agent. The device comprises a hollow tube having an interior surface and an exterior surface and a first end and a second end. A pharmacological agent is filled into the hollow tube for controllable release through the channels of the tube. Prior to the pharmacological agent being filled into the hollow tube, the first end is heat sealed, and after the pharmacological agent is filled into the hollow tube, the second end is heat-sealed. There are described in U.S. Pat. Nos. 5,324,519 and 5,599,552 biodegradable polymer compositions composed of a thermoplastic or thermosetting polymer that is injected into the body in a liquid injectable state. These compositions are used to prevent and treat disorders and diseases, such as bone or nerve growth disorders, and to alter body functions (e.g. as birth control). U.S. Pat. No. 5,599,552 further describes using the compositions to enhance regeneration of cells and tissue, such as bone and nerve cells, or for delivery of biologically-active substances to tissue or organs.
Thus, there are a number of drawbacks with currently available methods for treating eye disorders and diseases. For example, in the case of these posterior segment eye diseases, traditional routes of drug administration such as topical or oral dosing often fall short of reaching the disease site. As a result, current methods for treating back-of-the-eye diseases involve introducing drugs directly into the vitreous chamber of the eye via intraocular injections or intravitreal implants. The eye's natural circulatory processes rapidly remove solutions that are injected directly into the vitreous chamber. Subsequently, this approach often requires frequent, large dose injections which have been associated with complications such as glaucoma and cataract formation. Furthermore, large molecular weight molecules (>70 kD) are virtually incapable of traversing the tight junction complexes of the retinal pigment epithelium and retinal capillaries. Microparticle injections have improved the sustained release capabilities of conventional injections, but this still does not resolve the widespread distribution of the medication via intraocular convection. In the case of steroids, this distribution is known to lead to adverse effects such as glaucoma and cataract. Additionally, the eye's natural circulatory processes have a subtle anterior to posterior ocular convection, which results in lower drug concentrations at the back of the eye where the disease is developing.
It thus would be desirable to provide safe and effective methods for treating an eye, particularly treating “retinal and/or choroidal disorders or diseases, by delivering a therapeutic medium directly to the desired treatment site. In particular, it would be desirable to provide localized sustained delivery of a therapeutic medium at the retina and/or the choroid while minimizing such action in other tissues of the eye. It would be desirable to provide a method that minimizes trauma and eliminates the need for fluid dissection of the retina. It would further be desirable to provide a method that effectively lowers the dosage of therapeutics required for treatment. It would further be desirable to provide a method that reduces and even eliminates the side effects associated with intravitreal delivery of therapeutics. It would further be desirable to provide a method that effectively and efficiently delivers large molecular weight drugs and proteins to a treatment site.